Epidermal inflammation and aging are closely related phenomena. So similar are the processes involved with both, that aging is sometimes described dermatologically as a chronic low grade inflammatory condition. In acute inflammation, there can be a respiratory burst of neutrophil activity that initiates cascades that typically involve a change in the oxidation state of the cell. Acute inflammation is also characterized by mast cell degranulation wherein serotonin is produced, which acts as a signal transduction factor. Following that, excited oxygen species are generated, e.g., superoxide anion, and these damage the lipid-rich membranes and activate the chemical mediators of proinflammation and inflammation. Alteration in the redox state of the cell activates transcription factors such as NF.kappa.B as well as AP1, which then causes production of proinflammation mediators. These mediators, such as TF.alpha. and various interleukins, cause a burst of cytokines. Arachadonic acid is released, which is oxidized to biologically active mediators. When arachadonic acid is oxidized via the cyclooxygenase or lipoxygenase pathways, for example, prostaglandins, leukotrines, and hyroxyeicosatetraenoic acid (HETE) are produced, which cause erythma, edema, and free radical production. Transcription factors such as NF.kappa.B and AD1 alter DNA expression in the cell and produce cytokines and proteinases such as collagenase.
Similar metabolic events are observed in epidermal aging. Cell age is due in part to free radical damage, which takes place mostly within the cell membrane. The cell membrane is most susceptible to attack by free radicals because of its dense molecular structure largely comprising lipids and lipoproteins, which are easily oxidized by reactive oxygen species. In the epidermis, reactive oxygen species such as singlet oxygen, the superoxide anion, and hydroxyl radicals, as well as other free radicals, are generated in normal metabolism, as well as through ultraviolet sun exposure, other forms of radiation, other environmental factors such as pollution or exposure to chemicals in the home or workplace, and the like, active in the arachidonic acid cascade. As in inflammation, free radicals activate chemical mediators that produce prostaglandins and/or leukotrines.
The body contains an endogenous antioxidant defense system made up of antioxidants such as vitamins C and E, glutathione, and enzymes, e.g., superoxide dismutase. When metabolism increases or the body is subjected to other stress such as infection, extreme exercise, radiation, or chemicals, the endogenous antioxidant systems are overwhelmed, and free radical damage takes place. Over the years, the cell membrane continually receives damage from reactive oxygen species and other free radicals, resulting in cross-linkage or cleavage or proteins and lipoprotins, and oxidation of membrane lipids and lipoproteins. Damage to the cell membrane can result in myriad changes including loss of cell permeability, increased intercellular ionic concentration, and decreased cellular capacity to excrete or detoxify waste products. As the intercellular ionic concentration of potassium increases, colloid density increases and m-RNA and protein synthesis are hampered, resulting in decreased cellular repair. Some cells become so dehydrated they cannot function at all.
In aging, the regularity of tissue structure is lost. Individual cells enlarge, but the total number of cells decreases approximately 30%. The dermis microscars and diminishes with loss of elastic and collagen fibers. Cross-linking between longchain collagen macromolecules occurs. Elastin loses its discrete structure.
As mentioned above, at least some mast cell degranulation is observed in most acute pathological inflammatory processes. Upon being activated by any of a number of stimuli, mast cells degranulate, expelling secretory granule contents and releasing pharmacologic mediators. The consequences of mediator release may be apparent within minutes or may require hours to develop. Among the mast cell-derived mediators, either preformed within the granules or generated from precursor molecules, are kinins and kininogen, thromboxanes, leukotrienes C.sub.4, D.sub.4 and E.sub.4, easinophil chemotactic factors of anaphylaxis, heparin, superoxide dismutase mutase, prostaglandins, platelet-activating factor, neutrophil chemotactic factor of anaphylaxis, inflammatory factors of anaphylaxis, and a number of enzymes including proteinases such as chymotrypsin, trypsin, and collagenase. Serotonin is produced, which acts as a signal transduction factor.
Mast cell degranulation is observed in a number of pathological processes and conditions of the skin and mucosa. These include urticaria (hives), allergic conjunctivitis (an inflammatory disease of eye mucous membranes), allergic rhinitis (an inflammatory disease of nasal mucous membranes), atopic dermatitis, cutaneous mastocytosis (an abnormal increase in mast cells), and various allergic and immune complex-mediated inflammations. In all these, degranulation either causes or exacerbates symtoms of the malady, which even in mild cases include elevated, erythematous, pruritic wheals or serpiginous exanthem, usually surrounded by areas of erythema in hives; nasal stuffiness, paroxysms of sneezing, profuse mucous secretion and frequent itching of the nose and posterior pharynx in allergic rhinitis; and soreness or inflammation of the conjunctivae, with excessive tearing and mucoid conjunctival discharge and frequent itching of the eyes, in allergic conjunctivitis. Periodontal disease is an inflammatory disorder of the gums variously referred to as gum disease, periodontitis, and gingivitis; the disorder typically results from the accumulation of plaque, particularly within the gum line, which, unless effectively removed, produces a chronic inflammatory process of the gingiva that spreads and destroys the connective tissues supporting the tooth as well as the tooth itself. It is not uncommon for patients to exhibit fatigue, malaise, anorexia and irritability as a result of their uncomfortable pathological skin or mucosal conditions, and pronounced and chronic cases exhibit worse symptoms and can develop serious complications which are sometimes life-threatening.
A number of treatments have been suggested for symtomatic relief of these disorders. These include antihistamines and other decongestants, topical corticosteroids, systemic steroids, and, in the case of periodontal disease, a vigorous and sustained program of brushing and flossing. All have limitations and/or side effects. Uriticarias, for example, can be caused by a variety of agents including drugs, foods, food additives, inhaled and contact allergens, exposure to sun, heat, and cold, exercise, and different immune complex-induced and complement-related disorders, and so treatment of choice can vary a great deal among the different types depending upon the underlying diagnosis. Anti-inflammatory agents useful for some uriticarias may exacerbate others. Effictive removal of plaque is difficult in many cases of periodontal disease.
As summarized by Frost in U.S. Pat. No. 5,057,322, in a disclosure directed to the treatment of extreme mast cell disease such as urticaria pigmentosa and systemic mastocytosis, conventional therapy for mast cell disease is typically palliative and symtomatic, and includes transfusions, antimicrobials, antihistamines, adrenal steroids, corticotropin, roentgen irradiation, and nitrogen mustard (column 1, line 67 to column 2, line 2). Frost remarked that "[t]here does not currently exist any modality of drug treatment for mast cell disease" (column 2, lines 38 to 39), and suggested using an opioid antagonist such as naltrexone or nalmefene (id., lines 50 to 52).
Antihistamines have been suggested for the treatment of pruritic conditions such as contact dermatitis, allergic dermatitis, urticaria, insect bites, mast cell disease and reactions to intradermal allergy testing (U.S. Pat. No. 5,098,717 to Blackman, column 1, line 66, to column 2, line 2). Allergic rhinitis is commonly treated with antihistamines, but use of many of these causes sedation and excessive drying. Alpha-adrenergic agonists in nasal sprays and drops may yield initial relief to some patients, but use of these compounds for more than a few days often results in progressively severe nasal obstruction secondary to rebound swelling of the nasal mucosa. A 4% solution of cromolyn sodium (e.g., Nasalcrom.TM. and Opticrom.TM.) applied topically can also be beneficial in the treatment and prevention of allergic rhinitis and conjunctivitis if administered frequently. The PDR reports that cromolyn sodium inhibits mast cell degranulation which occurs after exposure to specific antigens by blocking calcium ion entry into mast cells, and has the advantage of having no intrinsic bronchodilator or antihistamine activity (Physicians Desk Reference, 52.sup.nd ed., Medical Economics Company, N.J., 1998, p. 2367). However, the beneficial effects of the nostril spray with this agent may not be noted until 2 to 4 weeks after initiation of the treatment, so there is a need for an antihistamine or decongestant before cromolyn's preventive effect becomes apparent. Ophthalmic solutions can become contaminated.
Topical corticosteroids have been employed in the treatment and prevention of allergic rhinitis, but these may cause local burning, irritation, and occasional epistaxis or mild nasopharyngeal candidiasis in some patients, and the drugs do not relieve ocular symptoms. Systemic steroids administered by a nasal inhaler are sometimes used, but there is substantial evidence that no effects occur in adults who use up to 800 .mu.g daily (approximately 16 inhalations), and these drugs must be used with caution in the presence of (possibly undiagnosed) viral and fungal nasal diseases in which there appears to be an associated defect in cell-mediated immunity.
It would be useful to have additional topical compositions for the treatment of acute epidermal and mucosal conditions involving inflammation, including those related to mast cell degranulation, especially for urticaria, atopic dermatitis, cutaneous mastocytosis, allergic conjunctivitis, and allergic rhinitis, as well as those observed after surgery or other trauma from accidents and the like. It would also be useful to have therapies directed to chronic conditions which function using the same or analogous biochemical pathways, such as aging, radiation-induced skin damage, and periodontal disease.